Pharmaceutical dosage forms containing naturally or synthetically derived steroidal hormones often contain a low dose of these active ingredients. In the present invention the dose of estradiol is significantly lower than what has so far been administered orally in the treatment of physical conditions associated with insufficient endogenous levels of estrogens in women.
According to U.S. Pat. No. 5,891,868 (Cummings et al.), the risk of bone fractures in postmenopausal women was reduced by administering transdermally about 20 μg of estradiol, or even less than about 20 μg of estradiol, per day. Transdermal administration resulted in effective serum levels in the range between 5 and 20 pg/ml, which remained within that range for an extended period of time. Cummings et al. also suggested to administer the exogenous estrogen by other suitable routes, for example by oral or parenteral administration, but Cummings et al. further stated that “the estrogen should be administered parenterally or transdermally rather than orally. The former routes of administration are preferred over oral administration because oral administration of estrogen may lead to increased levels of sex hormone binding globulin. Sex hormone binding globulin may diminish the beneficial effects of administering estrogen to postmenopausal subjects, particularly subjects exhibiting signs of osteoporosis or loss of bone mineral density”. Thus, oral administration of low doses of estrogens, such as estradiol, are considered problematic for the reason mentioned by Cumming et al.
Furthermore, it is generally considered problematic to apply oral administration of a low dose of an active agent in order to ensure constant and low serum levels in an individual for an extended period of time of up to 18 to 24 hours and to achieve this in a reproducible manner within a large population of women. In particular, it is considered problematic when administering the estrogen, estradiol, which, despite the fact that it is provided in micronised form, exhibits extremely low bioavailability. Thus, the bioavailability of micronised estradiol is only about 3-5% following daily oral administration of 1 to 3 mg of estradiol. This low bioavailability is mainly attributed to an extensive metabolism in the gut and in the liver. For that reason, it is to be expected that oral administration of a lower dose of estradiol results in an even greater loss of estradiol through this extensive metabolism since the ratio of metabolic enzymes to estradiol is considerably higher. Therefore, the skilled person would not expect that the correct low dose of estradiol, giving rise to constant serum levels in the range of 5-30 pg/ml, could be successfully determined by performing linear extrapolation of known serum levels resulting from daily oral administration of 1-3 mg estradiol.
When formulating a solid oral dosage form intended for immediate release of a low dose of a highly hydrophobic active ingredient, such as estradiol, the person skilled in pharmaceutical science would consider i) increasing the disintegration of the oral dosage form into smaller fragments, ii) increasing the release of the active ingredient into the gastric fluid, and iii) increasing the dissolution rate of the active ingredient in the gastric fluid so as to prevent that the active ingredient enters the lower intestinal tract before being absorbed in the upper intestinal tract, which is the primary site of absorption for large molecules.
In order to do so, the person skilled in pharmaceutical science would, as his primary option, choose to formulate the solid dosage form using micronised material of the active ingredient to provide a high surface area. The high surface area will then allow for a rapid dissolution.
As a second option, the scientist would formulate the solid dosage form using excipients promoting disintegration in combination with excipients promoting the wetting/solubilising of the active ingredient in water or in gastric fluid. Normally, the scientist would select polyvinylpyrrolidone (PVP), which is an excipient exhibiting solubilising effect (improving the wettability), but also binding capacity making this excipient a “first choice” option, in particularly, when formulating oral solid dosage forms of highly hydrophobic drugs. The solubilising effect of polyvinylpyrrolidone is well described in the literature. For example, polyvinylpyrrolidone has been shown to improve the solubility and dissolution rate of atenolol (Moneghini et al. Int J Pharm 175; 1998; 177-183) and to increase the dissolution of prednisolone, nitrofurantoine and nitrofural considerably from gels containing 1-10% w/w of polyvinylpyrrolidone (Voigt et al. Pharmazie 35; 1980:311-312).
WO 01/52857 describes manufacturing of oral dosage forms containing 1 to 3 mg of estradiol with polyvinylpyrrolidone 25000.
However, the present inventors have found that when a lower dose of estradiol is applied in a tablet formulation similar to those described in example 1 of WO 01/52857, a significant loss of estradiol during storage is detected, i.e. the estradiol is no longer chemically stable.
Therefore, the object of the present invention is to provide stable, oral solid dosage forms containing a low dose of estradiol without compromising rapid release and dissolution of estradiol in the gastric fluid so as to achieve reliable and sufficient low serum levels of estradiol for an extended period of time of about at least 18 to 24 hours following one single administration of said dosage form to a woman.
In other words, the object of the present invention is to provide oral solid dosage forms which comprise estradiol in a low dose and, at the same time, meet the following requirements:                Immediate release of estradiol in the gastric fluid following oral administration in order for estradiol to be absorbed in a highly bioavailable manner        Chemically and physically stable, in particular with respect to estradiol        Reliable and sufficient absorption of estradiol so as to achieve serum levels of estradiol that constantly remains in the range between about 5 and 20 pg/ml        High content uniformity        Preferably, the dose of estradiol is lower than previously applied in the treatment of postmenopausal women        
Prior art documents describing polyvinylpyrrolidone-free pharmaceutical compositions containing estrogens in low doses are described below.
WO 02/47692 describes a vaginal tablet composition containing 10-30 μg of estradiol. The vaginal tablets disclosed in WO 02/47692 are not suitable for oral use and the skilled person will immediately realise that estradiol will be slowly released from such vaginal tablet compositions.
WO 97/12600 (equivalent to U.S. Pat. No. 6,060,077) relates to vaginal capsules containing 2.5-15 μg of 17β-estradiol. Again, such vaginal compositions are not suitable for oral administration.
U.S. Pat. No. 6,326,366 broadly describes oral dosage forms comprising a mixture of from 0.2 to 5 mg of an estrogen, such as estradiol, and isoflavone. However, in the working examples, 0.625 mg of the estrogen is administered. The oral solid dosage forms of the present do preferably not contain isoflavone.
U.S. Pat. No. 3,318,925 describes pharmaceutical compositions comprising 7α-methyl estrone and 7α-methyl estrone 3-methyl ether in an amount of 50 μg.